Therapeutic Guideposts in Maintenance Therapy: Switching vs Continuing vs Observing Tracey Evans, MD Abramson Cancer Center University of Pennsylvania Philadelphia, PA

Which direction? For how long?

NCCN Guidelines Non-squamous Squamous

One Thing NOT to do: Continue Original Platinum-based Regimen Until Progression Comparison N PFS OS QOL/Toxicity MVP 6 vs 3 1 308 5 vs 5 mo (p=0.5) 7 vs 6 mo (p=0.2) Better in shorter arm P/Cb until PD vs 4 2 230 NR 8.5 vs 6.6 mo (p=0.63) No diff QOL/More neuropathy in more Cb/vin 6 vs 3 3 300 21 vs 16 wk (p=0.21) 32 vs 28 wks (p=0.75) No diff global QOL/more transfusions longer P/gem or tax 4 vs 2 more if no PD post 2 4 314 (69%) 6.2 vs 4.6 mo (p=0.001) 15.9 vs 14.9 mo (p=0.461) Von Plessen study showed less dyspnea in 6 arm Park study showed better “role functioning” in shorter arm 1: Smith et al. J Clin Oncol 19: 1336-1343 (2001) 2: Socinski et al. J Clin Oncol 20: 1335-1343 (2002) 3: von Plessen et al. Br J Cancer 95: 966-973 (2006) 4: Park et al. J Clin Oncol 25: 5233-5239 (2007)

What SHOULD you do? SWITCH MAINTENANCE CONTINUATION MAINTENANCE OBSERVATION Stop all anti-cancer treatment until disease progression Continue a portion of the initial treatment until disease progression Continue treatment until disease progression with an agent NOT part of initial regimen

OBSERVATION Pros Cons Had been the standard of care Easiest Cheapest Least toxic Cons Potential for undertreatment

Observation: Potential for Undertreatment Agents with established second-line benefits Docetaxel Pemetrexed Erlotinib Historically, only 40-50% of patients treated with first line therapy go on to second line therapy Earlier treatment may be BETTER

Switch Maintenance AKA Early Second Line Therapy Pros Guaranteed exposure to second-line treatment Cons Exposed to toxicities of two regimens Cumulative toxicity, inconveniece

Immediate vs. Delayed Docetaxel PD off study Immediate Docetaxel x 6 Stage IIIB/IV NSCLC PS 0-2 CbGem x 4 PD Docetaxel was given either immediately after completion of carboplatin/gemcitabine therapy (for maximum of 6 cycles) or at the time of progression (for maximum of 6 cycles) Delayed Docetaxel x 6 CbGem: Carboplatin/Gemcitabine Primary EP: Overall Survial CbGem: Carboplatin/Gemcitabine V. Fidias et al. J Clin Oncol 27: 591-598 (2008)

Immediate vs. Delayed Docetaxel PD off study Immediate Docetaxel x 6 Stage IIIB/IV NSCLC PS 0-2 N=153 CbGem x 4 PD Docetaxel was given either immediately after completion of carboplatin/gemcitabine therapy (for maximum of 6 cycles) or at the time of progression (for maximum of 6 cycles) Delayed Docetaxel x 6 N=566 N=309 N=156 Only 98 patients (63%) went on to receive cycle 1 In delayed arm. CbGem: Carboplatin/Gemcitabine Primary EP: Overall Survial V. Fidias et al. J Clin Oncol 27: 591-598 (2008)

Fidias et al. J Clin Oncol; 27:591-598 2008 Immediate (n=153) Delayed (n=154) LR p-Value Median PFS (mo) 5.7 2.7 <0.0001 12-month PFS, % 20% 9% Immediate (n=153) Delayed (n=154) LR p-Value Med OS (mo) 12.3 9.7 0.085 12-mo OS 51.1% 43.5% And these are the results. The median PFS was 5.7 months in the immediate arm, and 2.7 months in the delayed arm – a difference that was highly statistically significant. The 12 month PFS was 20% in the immediate arm, and 9% in the delayed arm. Fidias et al. J Clin Oncol; 27:591-598 2008

Pts Who Actually Received docetaxel Immediate vs. Delayed Docetaxel Median Survival Number Randomized Pts Pts Who Actually Received docetaxel Delayed Docetaxel 98 (63%) 9.7 mo 12.5 mo Immediate Docetaxel 145 (95%) 12.3 mo NA When one looks at the survival of the patients on the delayed docetaxel arm, one can see the median survival of those who actually received docetaxel was the same as for the patients who were randomized to the immediate arm. Analysis of those who went onto Docetaxel as “salvage” therapy suggests no compromise in longterm survival V. Fidias et al. J Clin Oncol 27: 591-598 (2008)

Immediate vs. Delayed Docetaxel Why were 58 pts (37%) assigned to delayed docetaxel arm never treated? disease progression (25), pt decision (12), death (5), investigator decision (4), study closure (2), adverse event (1), other (6), missing (3) What was the plan for follow-up in delayed arm? Physical exam, labs, toxicity, and QOL assessment every 3 weeks until PD, disease assessment every 3 mos until PD V. Fidias et al. J Clin Oncol 27: 591-598 (2008)

Switch Maintenance Pemetrexed Double-blind, Placebo-controlled, Multicenter, Phase III Trial Stage IIIB/IV NSCLC ECOG PS 0-1 4 prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD Randomization factors: gender PS stage best tumor response non-platinum drug brain mets Pemetrexed 500 mg/m2 (d1,q21d) + BSC (N=441)* Placebo (d1, q21d) + BSC (N=222)* 2:1 Randomization Primary Endpoint = PFS *B12, folate, and dexamethasone given in both arms V. Ciuleanu et al. Lancet 374: 1432-1440 (2009)

Switch Maintenance Pemetrexed: Progression-free Survival by Histology Non-squamous Squamous HR=0.47 (95% CI: 0.37-0.6) P <0.00001 HR=1.03 (95% CI: 0.77-1.5) P =0.896 Progression-free Probability Pemetrexed 4.4 mos Pemetrexed 2.4 mos Placebo 2.5 mos Placebo 1.8 mos Time (months) Time (months) V. Ciuleanu et al. Lancet 374: 1432-1440 (2009)

Switch Maintenance Pemetrexed: Overall Survival, Intent to Treat Pemetrexed 13.4 mos Placebo 10.6 mos Survival Probability Time (months) HR=0.79 (95% CI: 0.65–0.95) P =0.012 SD: HR 0.61 PR/CR: HR 0.81 V. Ciuleanu et al. Lancet 374: 1432-1440 (2009)

Switch Maintenance Pemetrexed: Overall Survival by Histology Non-squamous (n=481) Squamous (n=182) HR=0.70 (95% CI: 0.56-0.88) p =0.002 HR=1.07 (95% CI: 0.49–0.73) p=0.678 Survival Probability Pemetrexed 15.5 mos Pemetrexed 9.9 mos Placebo 10.8 mos Placebo 10.3 mos Time (months) Time (months) V. Ciuleanu et al. Lancet 374: 1432-1440 (2009)

Switch Maintenance Pemetrexed: Treatment-related Toxicities* Placebo (N = 222) % Grade 3/4 All grades Neutropenia‡ 3 6 Anemia 15 1 5 Leukopenia 2 Fatigue‡ 24 10 Anorexia 19 Infection Diarrhea Nausea Vomiting <1 9 Sensory neuropathy 4 Mucositis/Stomatitis 7 Early Discontinuation for Toxicity *NCI CTC version 3.0 ‡P <0.05 for grade 3/4 rates of neutropenia and fatigue V. Ciuleanu et al. Lancet 374: 1432-1440 (2009)

Switch Maintenance Pemetrexed: Treatment-related Toxicities* Placebo (N = 222) % Grade 3/4 All grades Neutropenia‡ 3 6 Anemia 15 1 5 Leukopenia 2 Fatigue‡ 24 10 Anorexia 19 Infection Diarrhea Nausea Vomiting <1 9 Sensory neuropathy 4 Mucositis/Stomatitis 7 Early Discontinuation for Toxicity *NCI CTC version 3.0 ‡P <0.05 for grade 3/4 rates of neutropenia and fatigue V. Ciuleanu et al. Lancet 374: 1432-1440 (2009)

Switch Maintenance Pemetrexed: Treatment-related Toxicities* Placebo (N = 222) % Grade 3/4 All grades Neutropenia‡ 3 6 Anemia 15 1 5 Leukopenia 2 Fatigue‡ 24 10 Anorexia 19 Infection Diarrhea Nausea Vomiting <1 9 Sensory neuropathy 4 Mucositis/Stomatitis 7 Early Discontinuation for Toxicity *NCI CTC version 3.0 ‡P <0.05 for grade 3/4 rates of neutropenia and fatigue V. Ciuleanu et al. Lancet 374: 1432-1440 (2009)

Switch Maintenance Pemetrexed: Treatment-related Toxicities* Placebo (N = 222) % Grade 3/4 All grades Neutropenia‡ 3 6 Anemia 15 1 5 Leukopenia 2 Fatigue‡ 24 10 Anorexia 19 Infection Diarrhea Nausea Vomiting <1 9 Sensory neuropathy 4 Mucositis/Stomatitis 7 Early Discontinuation for Toxicity *NCI CTC version 3.0 ‡P <0.05 for grade 3/4 rates of neutropenia and fatigue V. Ciuleanu et al. Lancet 374: 1432-1440 (2009)

Switch Maintenance Pemetrexed: Treatment-related Toxicities* Placebo (N = 222) % Grade 3/4 All grades Neutropenia‡ 3 6 Anemia 15 1 5 Leukopenia 2 Fatigue‡ 24 10 Anorexia 19 Infection Diarrhea Nausea Vomiting <1 9 Sensory neuropathy 4 Mucositis/Stomatitis 7 Early Discontinuation for Toxicity *NCI CTC version 3.0 ‡P <0.05 for grade 3/4 rates of neutropenia and fatigue V. Ciuleanu et al. Lancet 374: 1432-1440 (2009)

Switch Maintenance Pemetrexed: Systemic Post-Study Treatment Placebo (N=222) % Patients with post-study therapy 52 67 Most common post-study therapies Carboplatin 7 10 Cisplatin 5 6 Docetaxel 22 29 Erlotinib 21 Gefitinib 13 Gemcitabine 9 14 Paclitaxel 4 1 19 Vinorelbine 17 Higher rate of follow-up treatment on the placebo arm Balanced selection of therapies between arms and low rate of crossover V. Ciuleanu et al. Lancet 374: 1432-1440 (2009)

Stratify by EGFR IHC results SATURN: phase III trial of Sequential Tarceva (Erlotinib) in Unresectable NSCLC Switch Maintenance Erlotinib Tumor samples (mandatory) Stratify by EGFR IHC results Erlotinib 150mg/day PD Chemonaïve advanced NSCLC n~1,700 Non-PD n~850 4 cycles of 1st-line platinum-based doublet 1:1 Placebo Stratifications EGFR protein expression by IHC positive vs negative vs indeterminate Stage at randomization IIIb vs IV ECOG PS 0 vs 1 CT regimen cisplatin-gemcitabine vs carboplatin-docetaxel vs others Smoking status smoking vs former vs never Region PD Completed: 152 centers participated in 29 countries Primary endpoint: PFS (25% improvment) V. Cappuzzo et al. Lancet Oncol online as of May 20 25

Stratify by EGFR IHC results SATURN: phase III trial of Sequential Tarceva (Erlotinib) in Unresectable NSCLC Switch Maintenance Erlotinib Tumor samples (mandatory) Stratify by EGFR IHC results Erlotinib 150mg/day PD Chemonaïve advanced NSCLC n~1,700 Non-PD n~850 4 cycles of 1st-line platinum-based doublet N=438 1:1 N=889 N=1949 Placebo Stratifications EGFR protein expression by IHC positive vs negative vs indeterminate Stage at randomization IIIb vs IV ECOG PS 0 vs 1 CT regimen cisplatin-gemcitabine vs carboplatin-docetaxel vs others Smoking status smoking vs former vs never Region PD N=451 Completed: 152 centers participated in 29 countries Primary endpoint: PFS (25% improvment) V. Cappuzzo et al. Lancet Oncol online as of May 20 26

Saturn: Overall Survival Better on the Erlotinib arm 12 m vs 11 m ; p= 0.0088; HR 0.81 [0.70-0.95]; HR 0.77 [0.64-0.93] in IHC (+) pts (p=0.0063) Benefit not seen in mutation (+) pts Likely due to crossover Signif benefit in TSD wrt analgesic use and pain V.

SATURN: PFS and OS PFS OS V. Progression-free survival (PFS) (A, B) and overall survival (OS) (C, D) according to response to prior chemotherapy. CR, complete response; HR, hazard ratio; PR, partial response; SD, stable disease. Coudert B et al. Ann Oncol 2011;annonc.mdr125 V. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com

Saturn: Toxicity V. Erlotinib (N=433) Placebo (N=445) Grade ≥ 3 All grades One or more AE 12% 65% 1% 20% Skin issue 9% 62% 10% Rash 60% 8% Pruritis <1% 6% 2% GI issue 23% Diarrhea 18% 3% General Nutritional 5% Anorexia Infection V. Cappuzzo et al. Lancet Oncol online as of May 20

Saturn: Subsequent Treatment Erlotinib Placebo Any 71% 72% Taxane 30% 31% Antimetabolite 24% 23% Antineoplastic 16% 18% Platinum 9% 12% EGFR TKI 11% 21% V.

Continuation Maintenance Pros No new toxicity Ensures maximum benefit of given treatment Cons Cumulative toxicity May not be in as good shape second-line therapy

Drugs given as CONTINUATION MAINTANCENCE: Because we have ALWAYS done it that way Erlotinib, whatever line of therapy, given until disease progression Crizotinib, whatever line of therapy, given until disease progression Bevacizumab… Cetuximab…

ECOG 4599: Chemotherapy +/- Bevacizumab Overall Survival 0.0 0.2 0.4 0.6 0.8 1.0 Proportion Surviving 6 42 48 18 30 12 24 36 HR=0.80; P=0.013 Bev/PC 12.3 mo PC 10.3 mo Median Survival 1-year survival 51% vs 44% 2-year survival 23% vs 15% KEY POINT: Overall survival was significantly prolonged by the addition of Avastin to paclitaxel and carboplatin. ADDITIONAL INFORMATION A significantly higher percentage of patients in the Avastin group were alive at 12 months (51% vs 44.4%) and 24 months (23% vs 15.4%). The median OS was 12.3 months vs 10.3 months for the Avastin plus PC group vs PC alone. The HR was 0.80, with a 20% relative reduction in the risk of death; P=0.013. REFERENCE Avastin® (bevacizumab) [Prescribing Information]. South San Francisco, CA: Genentech, Inc.; 2009. Months V. Sandler. N Engl J Med. 2006;355:24.

E4599 Phase III Trial Design Bevacizumab 15 mg/kg IV q3w until progression of disease or unacceptable toxicity First-line treatment of patients with stage IIIB with malignant pleural effusion, or IV, or recurrent NSCLC (N=878) Bev + PC q3w × 6 Bevacizumab 15 mg/kg paclitaxel 200 mg/m2 carboplatin AUC 6 PC q3w × 6 carboplatin AUC 6 (no crossover permitted) Progression of disease or unacceptable toxicity KEY POINT: On the basis of the results of the phase II study, a placebo-controlled phase III trial was designed and conducted in the first-line setting for patients with histology other than squamous cell NSCLC. Stratified by: Disease stage Degree of weight loss Prior radiotherapy Measurable disease Endpoints: Primary OS Secondary Response rate PFS Toxicity ADDITIONAL INFORMATION The 15-mg/kg IV q3w dose was chosen on the basis of the results of the phase II study, which showed best improvements in median time to progression, confirmed response, and median survival. The trial randomized 878 patients to receive paclitaxel 200 mg/m2 plus carboplatin AUC 6 with or without Avastin. Patients in the placebo arm were not allowed to cross over and receive Avastin, unlike the phase II trial. Patients in the Avastin arm received paclitaxel 200 mg/m2 plus carboplatin AUC 6 and Avastin for 6 cycles and then Avastin 15 mg/kg IV q3w until progression or unacceptable toxicity. The primary endpoint of the trial was OS. The secondary endpoints were response rates, PFS, and toxicity. REFERENCE Avastin® (bevacizumab) [Prescribing Information]. South San Francisco, CA: Genentech, Inc.; 2009. AUC=area under the curve; IV=intravenous; OS=overall survival; PFS=progression-free survival. V. Sandler A, et al. N Engl J Med. 2006;355:2542-2550.

E4599 Maintenance: Postinduction PFS Edited JA 8/18/11 E4599 Maintenance: Postinduction PFS BV/CP nonprogressors CP nonprogressors HR (adjusted)=0.64; P <0.001 Proportion Progression Free Months Since Treatment Initiation 1.0 0.8 0.6 0.4 0.2 0.0 0.5 1 yr: 32% (n=82) 4.5 8 12 18 24 30 36 42 1 yr: 17% (n=21) Induction 18 wks V. Sandler, et al. Presented at IASLC. 2011 (abstr P3.216).

E4599 Maintenance: Postinduction OS Edited JA 8/18/11 E4599 Maintenance: Postinduction OS BV/CP nonprogressors CP nonprogressors HR (adjusted)=0.75; P=0.03 Proportion Surviving Months Since Treatment Initiation 1.0 0.8 0.6 0.4 0.2 0.0 0.5 4.5 8 12 18 24 30 36 42 1 yr: 75% (n=162) 1 yr: 69% (n=92) Induction 18 wks 2 yr: 34% (n=46) 2 yr: 25% (n=17) V. Sandler, et al. Presented at IASLC. 2011 (abstr P3.216).

FLEX: Overall Survival Pirker R et al. Lancet 2009, 373, 1525

FLEX: Cisplatin + Vinorelbine ± Cetuximab for Advanced NSCLC Edited KA – 7/27/11 FLEX: Cisplatin + Vinorelbine ± Cetuximab for Advanced NSCLC Cetuximab + cisplatin (80 mg/m2 d1) + vinorelbine 25 (30) mg/m2 d1, 8; q3w up to 6 cycles Eligibility: Stage IIIB/IV EGFR expressing Chemotherapy-naïve NSCLC (N=1125) Cisplatin (80 mg/m2 d1) + Cetuximab until PD or toxicity n=557 n=568 RANDOM I Z E Eligibility: ≥1 EGFR-positive cell All histological subtypes No known brain metastases Cetuximab: initial dose 400 mg/m2 then 250 mg/m2 weekly Primary endpoint: OS Secondary endpoints: RR, PFS, DCR, QOL, safety V. Pirker R, et al. Lancet. 2009;373:1525-1531. 39

Pemetrexed as Continuation Maintenance

PARAMOUNT Continuation Maintenance Pemetrexed Study Treatment Period Progression Induction Therapy (4 cycles) Maintenance Therapy (Until PD) 21 to 42 Days 500 mg/m2 Pemetrexed + 75 mg/m2 Cisplatin, d1, q21d CR, PR, SD PD Placebo + BSC, d1, q21d 500 mg/m2 Pemetrexed + BSC, d1, q21d 2:1 Randomization Patients enrolled if: Nonsquamous NSCLC No prior systemic treatment for lung cancer ECOG PS 0/1 Stratified for: PS (0 vs 1) Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD) Primary objective: progression-free survival Secondary objectives: Overall survival, response rate, pt reported outcomes, resource utilization, adverse events V.

PARAMOUNT Continuation Maintenance Pemetrexed Study Treatment Period Progression Induction Therapy (4 cycles) Maintenance Therapy (Until PD) 21 to 42 Days 500 mg/m2 Pemetrexed + 75 mg/m2 Cisplatin, d1, q21d CR, PR, SD PD Placebo + BSC, d1, q21d 500 mg/m2 Pemetrexed + BSC, d1, q21d 2:1 Randomization Patients enrolled if: Nonsquamous NSCLC No prior systemic treatment for lung cancer ECOG PS 0/1 Stratified for: PS (0 vs 1) Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD) N=539 57% N=359 N=180 N=939 Primary objective: progression-free survival Secondary objectives: Overall survival, response rate, pt reported outcomes, resource utilization, adverse events Paz-Ares et al, ASCO 2011, abstract CRA7510 V.

PARAMOUNT: Drug Administration (Randomized Patients) Maintenance Phase Pemetrexed (N=359) Placebo (N=180) Patients treated* 333 167 Number of cycles/patient Median 4 Range 1-19 1-16 Mean # of cycles 4.9 4.2 Patients completing >6 cycles 84 (23%) 25 (14%) Dose intensity 95% NA *Due to data cut off, some patients had been randomized but had not yet received maintenance treatment. V. Paz-Ares et al, ASCO 2011, abstract CRA7510 43

PARAMOUNT: PFS from Randomization V.

Time from Randomization (Months) PARAMOUNT: Final OS from Randomization Survival Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Pem Placebo OS Median (mo) (95% CI) 13.9 (12.8-16.0) 11.0 (10.0-12.5) Censoring (%) 28.7 21.7 Survival Rate (%) (95% CI) 1-year 58 (53-63) 45 (38-53) 2-year 32 (27-37) 21 (15-28) Pemetrexed Placebo Log-rank P = 0.0195 Unadjusted HR: 0.78 (95% CI: 0.64–0.96) 0 3 6 9 12 15 18 21 24 27 30 33 36 Time from Randomization (Months) Patients at Risk Pem + BSC 359 333 272 235 200 166 138 105 79 43 15 2 0 Placebo + BSC 180 169 131 103 78 65 49 35 23 12 8 3 0 V.

Time from Induction (Months) PARAMOUNT: Final OS from Induction 0 3 6 9 12 15 18 21 24 27 30 33 36 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Pemetrexed Median OS =16.9 mos (95% CI: 15.8–19.0) Placebo Median OS =14.0 mos (95% CI: 12.9–15.5) Log-rank P=0.0191 HR=0.78 (95% CI: 0.64–0.96) Survival Probability Time from Induction (Months) Patients at Risk Pem + BSC 359 335 276 234 200 164 138 106 77 42 15 2 0 Placebo + BSC 180 168 132 103 78 63 49 35 23 12 8 3 0 V.

Time from Randomization (Months) PARAMOUNT: Induction Response Subgroups OS Hazard Ratios All Randomized Patients (N=539) Stage IV (n=490) Stage IIIB (n=49) Induction Response CR/PR (n=234) Induction Response SD (n=285) Pre-randomization ECOG PS 1 (n=363) Pre-randomization ECOG PS 0 (n=173) Non-smoker (n=117) Smoker )n=418) Male (n=313) Female (n=226) Age < 70 (n=447) Age > 70 (n=92) Age < 65 (n=350) Age > 65 (n=189( Other Histologic Diagnosis (n=32) Large Cell Carcinoma (n=36) Adenocarcinoma (n=471) 0.78 0.79 0.82 0.81 0.76 Hazard Ratio CR/PR HR = 0.81 SD HR = 0.76 Time from Randomization (Months) Survival probability 0 9 18 27 36 0 9 18 27 36 Treatment Hazard Ratio (95%% CI) Favors Pemetrexed Favors Placebo V.

PARAMOUNT: Possible Drug-related CTCAEs* Maintenance safety similar to known profile of single-agent pemetrexed1,2 Pemetrexed (N=359) Placebo (N=180) Grade 1/2 % Grade 3/4 % Grade 3/4 % Fatigue† 17.5 4.7 10.6 1.1 Nausea 13.4 0.6 2.2 Anemia† 11.7 6.4 4.4 Vomiting 7.5 0.3 Mucositis/stomatitis‡ 5.8 Neuropathy/sensory 5.3 6.1 Neutropenia† 5.0 Leukopenia 2.8 ALT (SGPT) 2.5 * Data derived from the March 2011 safety update. Toxicities of any grade, occurring in ≥5% of patients in either arm, are listed, along with some select toxicities. †P<0.05 Fisher’s exact test of Gr 3/4 toxicities . ‡Combined term. V. 1Hanna N, et al. J Clin Oncol. 2004; 2Ciuleanu T, et al. Lancet 2009

PARAMOUNT: Post-discontinuation Therapy Pemetrexed (N=359) %* Placebo (N=180) %* Patients Receiving Post Discontinuation Therapy 64 72 Erlotinib 40 43 Docetaxel† 32 Gemcitabine 10 8 Vinorelbine 6 Investigational drug 4 Carboplatin 5 Paclitaxel 3 2 Cisplatin 1 *Data expressed as % of randomized patients. Systemic therapies used in ≥2% of patients in either arm are shown. †Only docetaxel usage differed significantly between arms (P=0.013). V. 49

Continuation Gemcitabine Comparison N (rand) PFS OS QOL/toxicity Gem vs BSC post cis/gem (III)1 206 (2:1, 59%) 3.6 vs 2 mos (p<0.001) 13 vs 11 mos (p=0.195) More transfusions in maint arm Gem vs BSC post cb/gem x 4 2 519 (49%) 3.9 vs 3.8 mo (p=NS) 8.0 vs 9.3 mo (p=0.84) More marrow suppression, fatigue in maint Gem vs Erl vs Obs post cis/gem x 4, all pem at PD (60% vs 63% vs 76%)3 834 (56%) 3.8 vs 2.9 vs 1.9 (p<0.0001 gem, p=0.002 erl) 12.1 (HR 0.88) vs 11.8 (HR 0.91) vs 10.7 mos (p=NS) More AE’s with gem than erl than obs Belani: large number of PS 2 pts (2/3) who did worse with maint, low post-study treatment rate (~17%), Dr. Kalemkerian “the most realistic study” Perol study allowed all hisotlogies, 17-22% squam 2nd line pem: 76% obs, 60% gem, 63% erl, third line obs 49.6% erl, gem 40.8% erl, erl 39% doc V. 1: Brodowicz et al. Lung Cancer 52: 155-163 (2006), 2: Belani et al, ASCO 2010, abstract 7506, 3: Perol et al, ASCO 2010, abstract 7507

Pemetrexed AND Bevacizumab as Continuation Maintenance

AVAPERL: Trial design V. R PD First-line induction 4 cycles, q3w Continuation maintenance q3w until PD Arm A: bevacizumab Previously untreated stage IIIB–IV nsNSCLC CR/PR/SD per RECISTc Bevacizumabb + pemetrexedb + cisplatinb R Arm B: bevacizumab + pemetrexed PD Stratification factors: Gender Smoking status Response at randomization Follow-up Primary objective: progression-free survival Secondary objectives: Overall survival, response rate, disease control rate, duration of response, duration disease control, safety, QOL bDose of bevacizumab = 7.5 mg/kg; dose of pemetrexed = 500 mg/m2; dose of cisplatin = 75 mg/m2. . V. Barlesi et al, ESMO 2011, abstract 34LBA 52

AVAPERL: Trial design V. N=376 N= 125 R N=253 67% PD N=128 First-line induction 4 cycles, q3w Continuation maintenance q3w until PD Arm A: bevacizumab N=376 Previously untreated stage IIIB–IV nsNSCLC CR/PR/SD per RECISTc Bevacizumabb + pemetrexedb + cisplatinb N= 125 R N=253 67% Arm B: bevacizumab + pemetrexed PD Stratification factors: Gender Smoking status Response at randomization N=128 Follow-up Primary objective: progression-free survival Secondary objectives: Overall survival, response rate, disease control rate, duration of response, duration disease control, safety, QOL bDose of bevacizumab = 7.5 mg/kg; dose of pemetrexed = 500 mg/m2; dose of cisplatin = 75 mg/m2. Barlesi et al, ESMO 2011, abstract 34LBA V. 53

AVAPERL: PFS from randomization 100 75 50 25 Bev+pem 7.4 months (81 events) Bev 3.7 months (104 events) HR, 0.48 (0.35–0.66); P <.001 Cont. maintenance bev+pem (n=128) Cont. maintenance bev (n=125) from date of randomization(%) Progression -free survival 0 3 6 9 12 15 Time (months) Pts at risk Bev+pem Bev 128 104 67 25 4 0 125 73 36 13 2 0 Median follow-up time in ITT population (excluding induction): 8.28 months (bev+pem arm), 7.95 months (bev arm) bev, bevacizumab; cont., continuation; HR, hazard ratio; ITT, intent to treat; pem, pemetrexed; pts, patients. 54 V. Barlesi et al, ESMO 2011, abstract 34LBA

AVAPERL: OS from induction 100 75 50 25 Bev+pem NR (34 events) Bev 15.7 months (42 events) HR, 0.75 (0.47–1.20); P=0.23 Overall survival (% of patients) Cont. maintenance bev+pem (n=128) Cont. maintenance bev (n=125) Data currently immature 0 3 6 9 12 15 18 21 Time (months) Pts at risk Bev+pem Bev 128 127 120 103 56 20 3 0 125 123 110 96 45 17 2 0 Barlesi et al, ESMO 2011, abstract 34LBA Randomized pts, Intent-to-treat population Median follow-up time: 11 months (8 months, excluding induction). 30% of events at the time of analysis for overall survival. bev, bevacizumab; HR, hazard ratio; NR, not reached; pem, pemetrexed; pts, patients. V.

Percentage of patients with Gr3-5 adverse event in maintenance phase AVAPERL: Summary of maintenance phase adverse events Percentage of patients with Gr3-5 adverse event in maintenance phase Bev, bevacizumab; Gr, grade; pem, pemetrexed V. Barlesi et al, ESMO 2011, abstract 34LBA

AVAPERL: Conclusions The AVAPERL trial met its primary endpoint of improved progression Impressive PFS benefit Both regimens were well tolerated OS data favors the continuation maintenance bevacizumab + pemetrexed but are currently immature V.

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ECOG 5508 Maintenance Trial Eligibility Bev- Eligible Treated Brain mets allowed PS 0-1 Bevacizumab R A N D O M I Z E Paclitaxel 200 mg/m2 Carboplatin AUC 6 Bevacizumab 15 mg/kg IV Q 3 wk X4 Pemetrexed Bevacizumab/ Pemetrexed N=1282 V. V.

Point Break (JMHD): Ongoing Phase III NSCLC Trial in First Line Edited EB – 5/4/11 Point Break (JMHD): Ongoing Phase III NSCLC Trial in First Line RANDOM I Z E Bevacizumab 15 mg/kg + pemetrexed/carboplatin q3w × up to 4 cycles Bevacizumab 15 mg/kg + paclitaxel/carboplatin Bevacizumab + pemetrexed Bevacizumab Eligibility: Stage III/IV NSCLC Nonsquamous No prior chemotherapy Treated brain metastases PS 0/1 Measurable disease Prior radiation allowed N=900 PD 1:1 Phase III Population: Stage IIIb-IV 1 EP: OS 2 EP: ORR, DCR, TTP, Safety Target Accrual: 900 Actual Accrual: 490 (1/29/10)   Sponsor: Eli Lilly and Company. PI: J Patel. Sites: 131. Enrollment complete. Primary endpoint: OS Secondary endpoint: PFS Superiority trial V. 60

Point Break (JMHD): Ongoing Phase III NSCLC Trial in First Line Edited EB – 5/4/11 Point Break (JMHD): Ongoing Phase III NSCLC Trial in First Line RANDOM I Z E Bevacizumab 15 mg/kg + pemetrexed/carboplatin q3w × up to 4 cycles Bevacizumab 15 mg/kg + paclitaxel/carboplatin Bevacizumab + pemetrexed Bevacizumab Eligibility: Stage III/IV NSCLC Nonsquamous No prior chemotherapy Treated brain metastases PS 0/1 Measurable disease Prior radiation allowed N=900 PD 1:1 N=292 62% N=472 Phase III Population: Stage IIIb-IV 1 EP: OS 2 EP: ORR, DCR, TTP, Safety Target Accrual: 900 Actual Accrual: 490 (1/29/10)   N=939 N=298 64% N=467 Sponsor: Eli Lilly and Company. PI: J Patel. Sites: 131. Enrollment complete. Primary endpoint: OS Secondary endpoint: PFS Superiority trial V. 61

PointBreak: KM OS from Randomization (ITT) Pem+Cb+Bev Pac+Cb+Bev OS median (mo) 12.6 13.4 HR (95% CI); P value 1.0 (0.86, 1.16); P=0.949 Censoring (%) 27.8 27.2 Survival rate (%) 1-year 52.7 54.1 2-year 24.4 21.2 V.

PointBreak: Subgroup OS Hazard Ratios V.

PointBreak: Kaplan-Meier (KM) PFS from Randomization (ITT) Pem+Cb+Bev Pac+Cb+Bev PFS median (mo) 6.0 5.6 HR (95% CI); P value 0.83 (0.71, 0.96); P=0.012 G4 PFS median (mo) 4.3 3.0 0.74 (0.64, 0.86); P<0.001 TTPD (mo) 7.0 0.79 (0.67, 0.94); P=0.006 ORR (%) 34.1 33.0 Censoring rate for Pem+Cb+Bev was 26.9; for Pac+Cb+Bev was 23.3 V.

PointBreak: Subgroup PFS (ITT) V.

PointBreak: Prespecified Analysis of KM PFS from Randomization: Maintenance Population Pem+Cb+Bev (n=292) Pac+Cb+Bev (n=298) PFS median (mo) 8.6 6.9 Censoring (%) 24.7 14.1 Prespecified exploratory non-comparative subgroup analyses V.

PointBreak: Prespecified Analysis of KM OS from Randomization: Maintenance Population Pem+Cb+Bev (n=292) Pac+Cb+Bev (n=298) OS median (mo) 17.7 15.7 Censoring (%) 36.0 30.2 V. Prespecified exploratory non-comparative subgroup analyses

PointBreak: Post-discontinuation Therapy (ITT ) Pem+Cb+ Bev (n=472) n (%) Pac+Cb+ Bev (n=467) P Value Patients Receiving PDT 250 (53.0) 276 (59.1) Docetaxel 99 (21.0) 38 (8.1) <0.001 Erlotinib 69 (14.6) 71 (15.2) 0.855 Carboplatin 68 (14.4) 56 (12.0) 0.290 Pemetrexed 66 (14.0) 169 (36.2) Bevacizumab 64 (13.6) 55 (11.8) 0.434 Gemcitabine 39 (8.3) 24 (5.1) 0.067 Paclitaxel 27 (5.8) 0.199 Cisplatin 20 (4.2) 8 (1.7) 0.033 Navelbine 16 (3.4) 15 (3.2) 1.000 Systemic therapies used in ≥3% of patients in either arm are shown. Docetaxel and Pemetrexed usage differed significantly between arms . V. 68

Percentage of Patients Getting Maintenance Therapy Study Induction Regimen Percent getting maintenance Fidias Carboplatin/gemcitabine 55% Saturn Platinum based doublet 46% Atlas Platinum based doublet/bevacizumab 66% Paramount Cisplatin/pemetrexed 57% Avaperl Cisplatin/pemetrexed/bevacizumab PointBreak Carboplatin/pemetrexed/bev> pem/bev 62% Carboplatin/paclitaxel/bev>bev 64%

Final Thoughts/Summation What is the best maintenance strategy? IT DEPENDS ON THE INITIAL TREATMENT REGIMEN IT DEPENDS ON THE PATIENT How they tolerate treatment Goals and priorities It depends on whether cost something we should be factoring in…..

Final Thoughts/Summation Continue oral agents, bevacizumab, and cetuximab until progression or until not tolerated If a patient is on a pemetrexed-based regimen and tolerating the pemetrexed well, strongly consider continuing until progression What to do if patients get BOTH first line pemetrexed and bevacizumab less clear Bev alone best tolerated, no evidence for stopping Continuing pemetrexed with it improves PFS, but not OS Strongly consider switch maintenance to pemetrexed or erlotinib after initial non-pemetrexed chemo Likely more beneficial in pts with SD first line